SK4998A3 - Transcorneal drug-release system - Google Patents

Abstract

The invention concerns a novel transcorneal drug-release system.

Description

Transcomomal system for controlled drug release, its micro-wall and its use

Technical field

The invention relates to a drug release system for the controlled release of drugs over a longer period of time.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention is directed to a transcorrenal drug delivery system with gastric tract bypass, which consists essentially of a device that allows the drug to be administered over a longer period of time by circumventing the corneal layers of the skin.

The device according to the invention consists essentially of a medicament reservoir and at least one - typically more - micro-barrel equipped with capillary openings which are connected to the reservoir so that the medicament, in the form of an active substance-containing solution, enters the reservoir into the micro-barrel . When the transcoreal system is applied to the skin, it microstensally penetrates through the stratum corneum and possibly the skin, allowing direct access to the innervated layer of the skin. In this way, the medicament can pass from the reservoir through the capillary openings in the micro-walls to the vascularized sections of the skin so that it can receive blood circulation there through the capillary circulation system. Microbrites can also be used instead of micro-bars, which will then scratch the skin when the system is deployed.

An essential advantage of the system according to the invention is that the main barrier to the transdermally applied drug substances - stratum corneum - is bypassed in the system according to the invention. It is the individually different properties of the topmost corneal layer in patients that cause problems such as insufficient bioavailability of the drug and allergy in the transdermal application of the active ingredients. A particular advantage of transcoreal administration is that this route of administration is not limited to active substances that penetrate the skin, such as

For example, in transdermal application. Suitable active ingredients are, for example, pain relievers - such as morphines, Naltrexone, fentanyl, oxymorphone; anti-Parkinson's agents - such as L-Dopa, pramipexole; circulatory drugs, nitroglycerin, antihypertensive agents and vasodilatory diseases such as clonidine, nifidepine, verapamil, diltiazam; anticoagulants such as heparin, hirudin; means for long-term therapy in cancer and immune system diseases; means for long-term treatment in addiction therapy; peptides; ACE inhibitors; neurokinin antagonists; hormones - such as estradiol.

The active substance is usually in the form of a solution in order to guarantee flawless transport through the capillary openings of the micro-walls of the transcomial system. In principle, any physiologically acceptable solvent or solvent mixture in which the active compound is dissolved in a sufficient amount can be used. Sufficient amounts are understood to be those concentrations of the active ingredient in the solvent that allow a therapeutically effective amount of the active ingredient to be administered.

Preferred solvents are water and ethanol. If necessary, solubilizers and complexing agents may be used to increase the solubility of the active ingredient in the solvent. Sensitive active substances may be supplemented with additives to increase storage stability.

The system of the present invention comprises a reservoir for storing a solution with the active ingredient, wherein the fluid conduit connection between the reservoir and the micro-walls allows the medicament to be delivered from the reservoir through the capillary openings of the micro-walls up to the stratum comeum so that the medicament bypasses the outer layers of the skin. can bring directly into the bloodstream.

Transport of the medicament - for example in the form of an aqueous solution - can take place on the one hand passively, i. as a result of the existing concentration gradient between the concentration of the active substance solution in the reservoir and in the blood, or active, for example, in the reservoir of the existing overpressure, electrostatic or capillary forces, or in the integrated pump system. Active transport of the active ingredient solution - for example by a pump or a piezoelectric membrane - is preferred. The volume flow rate (ml / time) of the drug can be adjusted,

-3resp. check one or more additional valves or throttle between the storage tank and the micro-walls.

Depending on the size of the reservoir, the concentration of the active ingredient as well as the therapeutic dose required, the transcoreal system of the present invention is suitable for a period of administration of from one to several days to 4 weeks or more, preferably 7 to 14 days.

In one embodiment, the system, in terms of its dimensions and weight, is so far miniaturized that it can be worn fastened to the skin and / or skin for a longer period of time without difficulty. in the skin - similar to a patch or bracelet. The attachment of the transcoreal system can be carried out by means of a bracelet, a skin-friendly adhesive or even micro-walls themselves.

The production of the system according to the invention as well as the filling of the reservoir are carried out under controlled conditions. For reasons of drug safety, the system according to the invention may be airtightly packaged or sealed until sterile conditions are used. sealed.

Typically, the reservoir and micro-sides of the system of the present invention form a single or multi-part structural unit in a single package. However, embodiments are possible in which the storage reservoir and the micro-stator are structurally separated from each other and connected to each other by a thin tube or capillary. This is particularly advantageous when larger amounts of drug are to be administered over a longer period of time.

Of decisive importance for the function of the transcoreal system of the present invention is the technical and constructional method of making microwalls, as well as capillary openings, which serve to deliver the active ingredient solution.

For penetration through the stratum corneum it is necessary that they have a micro-stiff length of at least 10 µm, preferably 50 to 100 µm, particularly preferably up to 1 mm. The micro-bones according to the invention are conical respectively. cylindrical, the radius of curvature of the prickles typically being in the region (µm, preferably less than 10 µm. This keeps the skin injury and pain sensitivity at application as small as possible. To ensure sufficient delivery of the active agent solution to the patient's capillary blood circulation, according to the invention, they have capillary openings, for example in the form of round holes or slits or combinations thereof.

Micro-sharpened material of defined porosity also allows the delivery of the active ingredient solution.

For example, special embodiments of the microwalls of the present invention may have capillary apertures in the form of a combination of a central aperture with outward slits.

Depending on the viscosity of the solution, the transport of the active substance solution can be promoted or reduced. regulated by mechanical, electrical, chemical and / or surface active sieves. For reasons of redundancy - but also to adjust the volumetric flow rate and conduction resistance - several micro-optics are preferably used for the transcoreal system. Usually, they are arranged micro-staggeredly on one surface that forms the side of the transcoreal system facing the skin. This area may be between a few square millimeters and a few square centimeters. The typical number of micro-sticks is between 10 and 100, and this is in no way intended to limit the inventive idea.

The material from which they are made micro-must be well-tolerated and biocompatible. In addition to ceramic materials, glass and metals - for example titanium - are suitable for cheap mass production. Preference should be given to easily processable plastics. Biodegradable polymers, such as polylactides and others, have the advantage that the spike material particles that eventually remain in the skin can be degraded. Biodegradable polymers are well known in the art and have proven to be, for example, sewing materials and bone rails.

I

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows a particularly simple transcoreal arrangement

I of the system 20 in axial section.

Fig. 2 shows another embodiment of the transcoreal system of the invention.

FIG. 3 shows embodiments of barbs.

Fig. 4 shows a tub-shaped reservoir 50.

Fig. 5 is a cross-sectional view of the transsome system 1.

-5Obr. 6 shows a number of embodiments of micro-bars according to the invention in cross-section and viewed from above.

Fig. 6a shows a micro wall with a central hole S and a cylindrical outer shape S and a conical tip.

Fig. 6b shows a micro-wall with a slot-shaped opening S and a cylindrical outer shape Srt.

Fig. 6c shows a micro-wall with flattened outer sides 8, the opening being arranged in the form of a slot.

Fig. 6d shows a micro-wall with a cylindrical outer shape and an angled tip 10.

Fig. 6e shows an embodiment of the microbrites according to the invention which can be used instead of micro-burrs, in cross section and viewed from above.

Fig. 6f shows an embodiment of a microbrit in the form of a grain with sharp, skin-scraping edges.

DETAILED DESCRIPTION OF THE INVENTION

Fig. 1 shows a particularly simple axial cross-section of the transcoreal system 26. The system consists of a container 21 with micro-walls 23 formed at the bottom 22. The interior of the container serves as a reservoir 24 for storing the active substance solution 25. Depending on the viscosity, the active ingredient solution is either present in the reservoir itself or embedded in a matrix, for example of absorbent material or polymer.

The container and the micro-stern have a liquid-tight outer wall 26 that is mechanically so stable that the drug release system can be attached to the skin and micro-sternly can be pushed into the skin by slight pressure. Since the outer wall 26 is interrupted in the region of the micro-prong tips 2 and forms an outlet 26, the active substance solution can enter the capillary blood circulation due to the capillary sfl with circumvention of the transominal skin layer and from there develop its systemic action. Optionally, an adjustment is provided in the reservoir area to achieve pressure equalization - vent 26 · Normally the vent is fitted with a filter to prevent dirt from entering the system. On the

-Supporting the volumetric flow rate of the active ingredient solution may be provided to provide a higher pressure in the reservoir. The filling of the system is carried out, for example, by injecting the active substance solution into the reservoir, immersing the system in the active substance solution or by inserting a matrix saturated with the active substance into the system. Of course, in the latter case, the transcoreal system is constructed as a two-part system, for example, from the lower part which it forms micro-stably, and from the upper part which closes the system after the active substance matrix has been fitted. Depending on the type of active ingredient, it may be in dissolved form in an aqueous or organic, physiologically acceptable solvent or solvent mixture. Suitable solvents are, for example, water, ethanol, propanol and mixtures thereof. However, the active ingredients can also be dissolved in a gel matrix - for example a polymeric material.

Suitable materials for the manufacture of the container and the micro-walls are, first of all, thermoplastics, which can, due to the fine-grained granulate, sinter to a certain shape. By suitable selection of pressure, temperature (typically below the melting point of the material) and time parameters, reproducible porosity (typically 50%) is set. Subsequent targeted melting of the surface of the component closes the component so as to form a porous container with a tight outer wall. The areas of the walls to be kept permeable, such as vent holes, micro-spike tips, are kept below the melting point by cooling. In addition, coatings and seals are also suitable for sealing porous walls which, however, require higher costs in terms of technical design. The degree of porosity and outlet cross-sections of the prick tips can be varied within certain limits and hence the parameters for adjusting the dosing rate. Other suitable materials are, for example, polyethylenes, polypropylenes or polysulfones.

Another embodiment of the system according to the invention is shown in FIG. 2. Transcoreal system 2Ω consists of a lower housing part 31a and an upper housing part 21b. The lower housing part 31a comprises, on the side facing the skin surface, a micro-bar 22 with capillary apertures 23, of which only three, but enlarged, are shown in the figure for better illustration. The reservoir 34 for the active substance solution consists of a movable piston 2Z and a bellows seal 23 on the sides to the bottom of the housing. The bellows seal can of course be replaced by other

By means of sealing means, for example by precisely guiding the piston in the lower housing part. The upper housing part comprises a micro pump 22 which exerts a defined pressure on the piston and thereby applies the active ingredient via micro-sticks to the capillary circulation system. Microvalves 22a may be provided in front of the capillary openings on the inside of the lower housing part to prevent premature drug release. The pressure on the piston can be applied pneumatically by the pump, but in another embodiment it can also be exerted by a miniaturized electric motor and a gear connected to it in a purely mechanical manner.

In order to improve the controllability and controllability of the active substance dosing, the system can be extended with micro-sensors 39c. microcontrollers 22fi, for example, for actively adjusting microvalves (not shown), electronic switching circuit 39b with two-position control 22d, and power supply. The sensors are primarily used to sense and control regulatory and disturbance variables, such as blood concentration of the drug, temperature or patient activity, and to sense and control system variables such as time, flow, pressure, temperature. The memory area of the electronic switching circuit is programmable by prescribed data and parameters by the supplier or physician, respectively. through appropriate interfaces. Measured sensor values are recorded by the electronics and further processed. Depending on the predetermined control and regulation function, the setting signals for the microcontrollers are derived from here.

An essential part of the transcoreal system of the present invention is the formation of micro-walls.

Embodiments of barbs 41 are shown in FIG. 3. FIG. Fig. 3a shows a porous at the tip and thus for the drug solution as a continuous retaining bar 41; 3b shows a bar 42 with a completely sealed outer wall. The tip comprises an extension 44 which breaks off at its root, the design point 42 of the predetermined breaking point, thereby opening the previously tight spike point at the fracture point. Another possibility of opening the prongs of the prongs is that the prongs of the spindles, initially closed by the sealing foil 45, are pulled apart upon breaking and the prongs of the prongs tear apart (FIG. 3c). In order to anchor the transcoreal system, backhooks can be formed on the spines, see fig. 3d. The spines are made essentially of a biologically compatible material such as metals, ceramics and

-8 polymers such as biodegradable polymers based on glycolide and / or lactide, preferably as copolymers with other biodegradable polymers. The spines may also be made of a porous active substance-permeable material, for example thermoplastics, so that the active substance will be transferred over the entire surface of the spines.

Fig. 4 shows a tub-shaped reservoir 50 in which the active substance solution 41 is closed outwardly by the elastic membrane 54. According to an embodiment of the transcoreal system of the present invention, the storage reservoir and the micro-intruding skin 53 form a structural unit. The walls 55 of the reservoir and the barbs 53 are, as described above, of porous material, the surface of which is sealed on the outside. The active ingredient solution is injected into the active ingredient matrix 52 under slight positive pressure. The positive pressure is maintained by the elastic membrane 54 and is thus available to maintain a constant flow. The flow rate can be increased from the outside (patients) by pressing the diaphragm for a short time to allow an additional dose. Fig. 4a shows the system according to the invention in the initial state, the outwardly curved membrane 54 ensures that the active substance solution is pressurized and is injected into the active substance reservoir 52. The active ingredient is passed through the microstructure 53 through the transcomenal skin layer to achieve a systemic effect. Fig. 4b shows the membrane 54 after most of the drug solution has been consumed.

Fig. 5 shows a cross-section of the transcoreal system 1. The housing 1Ώ contains a reservoir 2 of active substance which is closed by a moss on its upper side.

3. In the reservoir there is an active substance solution 4 which, on the underside of the active substance reservoir, passes through the inlet channel 5 into the pump chamber 5. Via the outlet channel Z the active substance solution reaches the micro-walls 5 arranged on the underside of the housing. and from there through the capillary openings 5 micro walls out. The housing side parts 15a and the housing bottom parts 10b together with the micro-walls form a structural unit, preferably of thermoplastic. The housing cover comprises a battery power supply 11 as well as an electronic control 12, the ventilation 13 allowing the moss to adapt to this decreasing volume when the active substance solution is transferred by the micro-walls. The active substance solution is transported by means of a piezoelectric membrane 14 which:

-9 performs an electrically controlled pumping movement. The inlet channel S is shaped in such a way that the active substance solution is pumped through the piezoelectric membrane 14 to the micro-bar outlets. This is done either by a valve or in that the cross-section of the inlet channel is smaller than the cross-section of the outlet channel Z. Before use of the transcoreal system, they are micro-protected by a barbed guard 15, for example in the form of a closure.

Fig. 6 shows a number of embodiments of micro-bars according to the invention in cross-section and viewed from above. Fig. 6a shows a micro wall with a central hole S and a cylindrical outer shape S and a tapered tip 1Ώ. Fig. 6b shows a micro-wall with a slot-shaped opening S and a cylindrical outer shape

FIG. 6c shows a micro-wall with flattened outer sides S, the opening being arranged in the form of a slot. Fig. 6d shows a micro-wall with a cylindrical outer shape and an angled tip 10. Fig. 6e shows an embodiment of the microbrites according to the invention which can be used instead of micro-burrs, in cross section and viewed from above.

The active substance solution openings S are usually located close to the lip S at the bottom 10b of the reservoir (see FIG. 5), so that the active substance solution can pass through the scratched skin surface and can exert its systemic action.

Fig. 6f shows an embodiment of a microbrit in the form of grain with sharp, skin-scraping edges Sh. The opening (s) S is located near the grain. The dimensions of the microbrits are of the order of approximately the same size as those previously described.

Individual microelectric, respectively. the microbrites are typically arranged on the underside of the transcoreal system and form a structural unit; for example, between 10 and 100.

Drug dosage can be controlled by volumetric flow rates, which in turn depend on the sum of the cross-sectional apertures in the micro-walls.

Claims (14)

CLAIMS 1. Transsome drug controlled release system, characterized in that it contains a reservoir of the active substance as well as a device with micro-walls or microbrites for the application of the active substance. 2. The transsome system according to claim 1, characterized in that the microstructure resp. the microbrits have a length (depth) which corresponds at least to the thickness of the corneal layers of the skin. 3. A trans-domed controlled drug delivery system comprising a reservoir of the active ingredient as well as a device with micro-walls through which the active ingredient is applied in the form of a solution. 4. The transsome system according to claim 1, 2 or 3, characterized in that it comprises a plurality of micro-sides on the skin-facing side. 5. The transsome system according to any one of the preceding claims, characterized in that it comprises a device which enables the active substance to be conveyed from the reservoir through the openings in the micro-walls to the skin. 6. A transdomome system according to any one of claims 1 to 5, comprising a power supply device for the system. A transdomome system according to any one of the preceding claims, characterized in that it comprises devices for controlling and controlling the release of the active substance. 118. The transcomial system according to any one of the preceding claims, characterized in that at least one boundary surface of the reservoir is movable. 9. A micro-wall for the application of drug solutions, characterized in that it has a length of at least 10 [mu] m. 10. The micro-wall of a transcome system according to any one of claims 1 to 8, characterized in that it has at least one capillary opening in the form of holes (s) and / or slits (s). Micro-wall according to claim 9 or 10, characterized in that it is an integral part of the active substance reservoir. A micro-wall according to any one of claims 9 to 11, characterized in that it consists of a thermoplastic. A micro-wall according to any one of claims 9 to 12, characterized in that it has a tip with a radius of curvature of less than 10 µm. A micro-wall according to any one of claims 9 to 13, characterized in that it consists of a porous, liquid-permeable material. Use of the transcomial system according to claims 1 to 8, for the controlled release of systemically acting drugs.